Fibromyalgia (FM) is a common rheumatic condition with core symptoms of musculoskeletal pain and fatigue (1,2). Specifically, FM is a group of common nonarticular rheumatic disorders characterized by achy pain, tenderness, and stiff muscles, tendon insertion areas and adjacent soft-tissue structures (47). Although patients with this condition are readily recognized, there is an ongoing controversy as whether it is or should be considered a distinctive pathophysiological entity (3). As most FM patients have multiple somatic complaints such as irritable bowel syndrome, unexplained paresthesia, cold intolerance, recurrent headaches and intermittent cognitive problems (4), it seems intuitively unlikely that a single etiologic mechanism is at play (5).
FM occurs mainly in females. It may be induced or made more intense by physical or mental stress, insufficient or subpar sleep, trauma or exposure to cold or dampness. It further may have its origin in or be intensified by a systemic disorder, usually rheumatic in nature, or a viral or other systemic infection, such as Lyme disease (47).
Rheumatoid arthritis (RA), on the other hand, is a chronic autoimmune disease characterized by non-specific but usually symmetric inflammation of peripheral joints. RA has the potential for causing progressive destruction of articular and periarticular structures. An unknown initiating agent causes an autoantibody response that is responsible for joint destruction and the concomitant symptomology of RA.
Polymyalgia rheumatica (PMR) occurs in females more than males by a 2:1 ratio and is more prevalent in people greater than 50 years old. PMR is characterized by severe pain and stiffness in proximal muscle groups, particularly those in the neck, pectoral and pelvic girdle regions. PMR is distinguished from RA by a lack of synovitis, erosive or destructive disease, rheumatoid factor or rheumatoid nodules.
It has been suggested that there is an intimate link between disordered sleep and a heightened awareness of pain (6,7). Although the mechanisms of such an association is not well understood, it could be relevant to a more complete understanding of the FM syndrome. Most FM patients have non-restorative sleep, i.e., they wake up feeling unrefreshed (8), and this has been associated with frequent awakenings and, in particular, alpha intrusion during non-REM sleep (9). Growth hormone (GH) is maximally secreted during stages 3 and 4 of non-REM sleep (10) and this led to the notion that FM patents may have impaired GH secretion (11). Low levels of insulin-like growth factor 1 (IGF-1) in patients with FM has been previously described (12, 48); two recent reports support this finding (13,14).
My current study was initiated to attempt to answer the following questions: (i) can the previous observation of low IGF-1 in FM be replicated in a larger cohort of patients? (ii) what are IGF-1 levels in other rheumatic diseases? (iii) do IGF-1 levels in FM patients vary with time? (iv) are low IGF-1 levels due to an impaired secretion of GH? (v) do medications or the clinical features of FM contribute to low IGF-1 levels? (vi) can FM patients, with low IGF-1 levels, secrete GH in response to standard provocation testing?
To answer these questions, I undertook to investigate the serum levels of IGF-1 in patients with fibromyalgia (FM) compared to healthy controls and patients with other rheumatic diseases, including RA, and to explore possible mechanisms for low IGF-1 levels in patients with FM.
Five hundred primary FM patients and 152 controls (56 healthy blood donors, 26 myofascial pain patients and 70 patients with other rheumatic diseases) were studied. All had measurements of acid-extracted serum IGF-1. A subset of 90 FM patients were evaluated for clinical features that might explain low IGF-1 levels. Twenty-five FM patients underwent growth hormone (GH) provocation testing with L.DOPA and clonidine. Fifty FM patents with proven GH deficiency, were blindly randomized into two groups and gave themselves either daily GH or saline injections and IGF-1 levels were measured monthly for 9 months
The mean serum IGF-1 level in FM patients was 138.+-.56 ng/ml and in the controls was 215.+-.86 ng/ml (p=0.00000000001). Low levels of IGF-1 were not due to depression, tricyclic medications, NSAIDS, poor aerobic conditioning, obesity or pain level. In general, patients with focal myofascial pain syndromes had normal IGF-1 levels (249.+-.70), as did patients with other rheumatic disorders, unless they had concomitant FM. Fibromyalgia patients with initially normal levels often had a rapid decline of IGF-1 over a period of one to two years Patients receiving daily injections of GH experienced a two to three fold increase in IGF-1 levels. Most FM patients with low IGF-1 levels failed to secrete GH in response to stimulation with clonidine and L.DOPA.
A significant finding from my study is that an analysis of variance for all categories, omitting age as a factor, suggests that patients with RA and patients with PMR can surprisingly have suboptimal IGF-1 levels that are not significantly different from the FM patients, even though the etiologies of each disorder appear to be distinct. The results of my study further indicate that hypothalamic-pituitary axis dysfunction is responsible for impaired GH secretion which leads to the low IGF-1 levels.